An Experimental Treatment Approach for Inflammation-Induced Depression PROJECT SUMMARY/ABSTRACT Depression is a major public health burden, and is even more prevalent and disabling in individuals with heightened inflammatory states due to certain diseases or treatments. Compelling evidence suggests that inflammation plays a causal role in the onset or perpetuation of some forms of depression including those in the context of interferon treatment, chronic diseases, aging, and obesity. Antidepressant medications?the mainstay of the current depression treatments, with limited efficacy, substantial adverse effects, and poor adherence?have consistently shown an even more limited efficacy in this inflammatory subtype of depression. Consequently, anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs, cytokine antagonists) have been tested for the treatment of inflammation-associated depression. However, these drugs have shown limited efficacy, substantial risk profile, and prohibitive cost. Thus, novel and safe pharmacologic strategies that target mood-specific mechanisms of inflammation-associated depression are needed. One of the potential mechanisms by which inflammation causes depression is via kynurenine metabolism. Inflammation activates the tryptophan-kynurenine metabolic pathway, converting tryptophan to kynurenine. Kynurenine produced in excess at the periphery can be transported into the brain, where it is metabolized into neurotoxic kynurenine metabolites responsible for the development of depressive symptoms. As this transport system across the brain-blood barrier makes use of the large amino acid transporter LAT1, it is theoretically possible to block kynurenine entry into the brain by administering competing amino acids such as leucine. Preclinical experiments confirmed the inhibitory effects of leucine on inflammation-induced depression as a result of the blockade of excess kynurenine from entering the brain. The overarching objective of this innovative proof-of- concept trial is to test whether leucine pretreatment abrogates acute depressive responses to an inflammatory challenge (i.e., endotoxin) in humans, relative to placebo pretreatment. This study hypothesizes that, compared to placebo pretreatment, leucine pretreatment will attenuate depressive responses to endotoxin. In this double-blind randomized placebo-controlled study of healthy volunteers (N=90; 18-65 y), we aim to examine the effects of leucine vs. placebo pretreatment on: 1) endotoxin-induced depressive symptoms (primary outcome); 2) negative affect responses to endotoxin (feelings of social rejection, negative bias in facial emotion recognition); and 3) positive affect responses to endotoxin (feelings of social acceptance, reward learning). If the hypotheses are confirmed, the involvement of the kynurenine pathway in the induction of depressive symptoms will be demonstrated for the first time in a human experimental study. This study will also provide instrumental information in designing future clinical trials of leucine to treat or prevent inflammation- associated depression.